ABSTRACT Asthma affects boys more than girls, but gender-switch occurs after puberty and asthma is more common in women than men. This research proposal investigates gender effect(s) on asthma severity. The long-term goal of our studies is to identify sex related differences in genetic risks and biological pathways of severe asthma. Our analyses of large databases reveal that severe asthma exhibits a bimodal peak in young boys and middle age women [1, 2], which pointes to sex hormones in mechanisms of asthma severity [1]. Preliminary data of sex hormone levels in participants with asthma from the Severe Asthma Research Program (SARP I&II; 2001- 2012) shows that men with both low progesterone and low testosterone and women with low testosterone and high estradiol have the most severe airflow limitation. Additionally, our genome-wide association analyses of single nucleotide polymorphism (SNP) x sex interaction and candidate gene analyses of European American adults with asthma in SARP I & II shows sex-specific genetic associations with percent predicted FEV1, a marker of severe asthma. Based on the findings, we hypothesize that risk of severe asthma is gender dependent due to variation in levels of male and/or female sex hormones over the lifecourse and the consequent interactions of sex hormones with asthma risk variants that result in a bimodal peak of severe asthma in boys and women. In aim 1, we will assess SNP sex interactions across the whole genome using genome wide interaction study (GWIS). We will also use a candidate gene approach, which will determine SNP x sex interactions in previously described asthma severity gene loci, such as lung function and immunity pathway genes. In aim 2, we investigate the effect of variations in sex hormone levels on the risk for severe asthma differentially in males and females. Equally important and parallel to the research plan, the career development plan is constructed for didactic coursework, one-on-one education and career guidance from strong mentors and collaborators expert in asthma, endocrinology, and analytical genetics. This research will be performed in the laboratory of Dr. Erzurum, Lerner Research Institute (LRI), Cleveland Clinic, and will be advised by experts in genomics and biochemical pathways unique to asthma. The LRI offers the ideal intellectual and research environment for success. The proposed research is innovative and significant as it may lay the groundwork for the care of patients with severe asthma in a personalized, gender specific way. Altogether the award will provide the candidate the knowledge, hands-on experience, expertise and productivity to develop into an independent physician-scientist focused on patient-centered mechanistic research.